Our long-term goal is to rapidly and efficiently identify novel molecules that eradicate head and neck cancers when applied alone and in conjunction with ionizing radiation. The goal for this R21 Exploratory proposal is to establish an efficient, unbiased screening method that will identify radiation sensitizers in a true in vivo setting. Head and neck cancers (HNC) remain extremely difficult to control even with high doses of radiation. Combinations of chemotherapy and radiotherapy have improved local-regional control and patient survival, but at the expense of morbidity. Current focus is on exploring new combinatorial therapies that perturb growth and angiogenic signaling pathways in order to optimize the therapeutic ratio (tumor control/normal tissue toxicity), albeit with an empirical approach. Our goal is to screen from the onset for agents that block critical aspects of cancer cell biology and enhance the effectiveness of radiation in a disease setting such as HNC. Cell-based screens fail to recapitulate the precise tumor environment and may therefore miss useful radiosensitizers. Current in vivo models such as xenografts in mice are costly and cumbersome for rapid screening of new compounds. Radiation responses in Drosophila melanogaster show similarities to radiation responses of tumors, and suggest that Drosophila may be an applicable model. For example, ionizing radiation induces p53-mediated apoptosis, but cell proliferation ensues to compensate and to confer resistance and survival of tumors (in mammals) and organ precursors (in fly). Microtubule poisons that interfere with cell proliferation sensitize Drosophila and human tumors to radiation, while growth factor signaling confers resistance to radiation in both Drosophila and human tumors. The usefulness of a Drosophila model as a rapid screening tool for identifying radiation sensitizers that translate to human cancers will be tested in 2 aims. Aim 1 will be to validate the effect of known radiation sensitizers of human HNC models for their ability to sensitize Drosophila to ionizing radiation. Aim 2 will be to identify, through small molecule libraries, radiosensitizers of Drosophila, and determine their ability to radiosensitize human HNC xenografts. Successful completion of this project would establish a novel, rapid and effective primary screen in vivo for radiosensitizers with potential therapeutic value. [unreadable] [unreadable] [unreadable]